1. Field of the Invention
The present invention provides compositions and methods for modulating cutaneous and mucocutaneous or mucosal proliferations that are benign or malignant, which are of viral origin such as common warts and plane warts. The methods and compositions disclosed herein provide for the treatment and prevention of a variety of damaged epithelial and mucosal tissues, particularly those resulting from hyperplastic or neoplastic conditions, especially those having a papillomavirus as a causative agent. For instance, it will be evident that the method will find ready application for the therapy or prophylaxis of, for example, verrucous lesions such as verruca plana, verruca acuminata, and other verruciform lesions marked by proliferation of epithelial cells. The subject compositions can also be used in the treatment of other epithelial proliferative or systemic disorders caused by wart viruses. For example, bowenoid papulosus is a tumor of the genitalia induced by premalignant wart viruses and usually afflicting men. Condylomatous dysplasia and cervical carcinoma in situ are premalignant tumors of the female genitalia, also induced by wart viruses. Known treatments for all these tumors are painful and not always effective. According to the present invention, such therapies can be augmented or replaced by treatment with the subject preparations.
2. Introduction
Dermatosis is generally used to describe any disease of the skin. Keratosis and Hyperplasia are generally used to describe those characterized by an overgrowth of the epithelium. In particular, these diseases include what are commonly referred to as warts, corns and calluses.
A wart (also known as verrucas) is a small flesh-colored usually hard tumorous growth of the skin which is characterized by circumscribed hypertrophy of the papillae of the corium, with thickening of the malpighian, granulation and keratin layers of the epidermis. Verucca vulgaris, a subset of warts or verruca, is characterized by infection of the keratinocytes with human papillomavirus.
Warts are a very common superficial lesions and tumors of the skin of benign, premalignant and malignant type. They are defined as a small intra-epidermal papillomatous growth which occurs on the surface of the skin of an animal body, with generally warts being common within humans of all ages. Papillomas (warts) have been detected based upon their histological characteristics at numerous sites in humans on the skin and the mucous membranes including the hands, face, feet, larynx, genitalia, genital tract, respiratory tract, and oral cavity.
Warts are caused by various human papillomaviruses through direct contact with the virulent particle. Warts are infectious and can be autoinoculated and spread to other individuals by direct contact. Each papillomavirus is related to a specific clinical presentation of the wart as shown in Table 1. Representative examples of wart conditions include benign cutaneous warts and in particular common warts (verruca plana) and plantar warts (verruca plantaris), Butcher's common warts, epidermodysplasia verruciformis (EV), flat (non-condylomatous) warts, plane or intermediary skin warts, genital (such as penile, anal, labial, and cervical) warts, seborrhoic warts (verruca senilis), juvenile warts (verruca plana), verruca vulgaris, intra-epithelial neoplasias and papillomas.
Verrucae warts are lumpy typically flesh colored and have rough surface. Finger-like projections and sometimes dark specks are present, which are the result of thrombosed capillaries. Usually these warts are found on the face and scalp. Plantar warts are found on the planter surface of the feet and can be deep and painful. These warts occur singularly, in clusters or spread over a wide area. Flat warts are typically small, flat-topped, flesh colored papules that occur primarily on the face, hands and forearms. Usually the surface of the wart is smooth and they may appear in the hundreds. Genital warts are soft, flesh colored or slightly pigmented and occur in the genitalia of the mammal and are sexually transmitted. Chronic infections of the viruses that cause genital warts in women are a serious problem as intra epithelial neoplasia or squamous cell carcinoma may develop.
HPV infection is a systemic rather than just a localized skin manifestation. The risk of infection of warts depend not only the virulence of the virus particles, but also on the patient's susceptibility to viral attack and strength of the patient's immune system. Immunodeficient patients have greater susceptibility to infection, inadequate treatment for HPV, and frequent recurrences. States of immunocompromization created by conditions such as pregnancy, organ transplants, chemotherapy, stress, old age, infancy, illness, or infections are risk factors for wart recurrence. All patients with HPV will be vulnerable to recurrences for the rest of their lives. Recently, it has also been observed that individuals with depressed immune systems, such as sufferers of Acquired Immune Deficiency Syndrome (AIDS), are prone to (HPV) infections which can result in tumor growth over their entire bodies, resulting in great mental and physical distress to the afflicted individual.
Host immune responses to papillomavirus infection are not well understood but infection usually occurs in the young, followed by persistence of the wart for a variable period of time. After spontaneous regression, if at all, the host is left immune to reinfection by the same virus. In humans, antibody response to HPV infection is characterized by the appearance of IgM antibodies prior to the onset of regression. Just subsequent to regression, both IgM and IgG antibodies are present; long after regression, only IgG is detectable. This conversion from IgM to IgG has been observed in cattle experimentally infected with Bovin Papillomavirus (BPV) as well.
In humans, regressing flat warts demonstrate a similar histological appearance with perivascular infiltration of mononuclear leukocytes in the upper dermis, with epidermal invasion sharply confined to the papilloma. This simultaneous regression of multiple warts at distant sites suggests that cell-mediated immunity plays a major role in papilloma rejection. Regression of flat warts, however, has no effect on plantar or palmar warts in the same individual, indicating that regression is HPV type-specific. A similar differential regression of warts has also been observed in cattle infected with multiple BPV types.
Untreated or recurrent anogenital warts can be transmitted not only sexually, but from infected mother to her child. HPV has been found in the amniotic fluid from some pregnant women with cervical lesions. This very early transmission source as well as the presence of warts in the birth canal can lead to the development of life-threatening laryngeal papillomas. These may not develop at birth but can develop anytime during the first few years of a child's life, the median age being 3 years of age. There are also cases of newborns with anotenital warts present at birth or developing them in the first few years after birth. Autoinoculation and fomite transmission are other vehicles of non-sexual transmission of the genital human papillomavirus infection. Active genital warts can be identified in approximately 2.5% of pregnant American women, thus being implicated in 60,000 to 90,000 pregnancies annually. HPV infections are more than twice as prevalent in pregnant women. Each year there are an estimated 1,500 new cases of laryngeal papillomatosis, indicating that the risk of infection from mother to newborn ranges from 1:80 to 1:200.
Papillomaviruses (PVs) are members of the papovavirus (PPV) family. PVs are a heterogeneous group of closely related small (50-60 nm) nonenveloped double-stranded covalently closed icosahedral DNA molecules. Papillomaviruses replicate in the nucleus of squamous epithelial cells and cannot be multiplied by culture. Although differing very much from each other, PV's have molecular sizes of the order to 7,000-8,000 base pairs and their genomes do nonetheless exhibit certain degrees of homology.
Papillomaviruses may be classified into distinct groups based on the host that they infect. The complete nucleotide sequence and genetic organization of a number of animal and human PV's have been determined including the human papillomavirus (HPV), cottontail rabbit papillomavirus (CRPV), equine papillomavirus (EPV) and Bovine papillomavirus (BPV).
Papillomaviruses are spread widely throughout nature and can produce a spectrum of diseases in a variety of higher vertebrates. They have been detected and isolated from humans, cattle, sheep, dogs, cats, rabbits, monkeys, snakes, horses, cows, deer and several avian species.
Papillomaviruses are remarkably species specific infective agents; a human papillomavirus cannot infect a nonhuman animal. Because the genomic organization is highly conserved among papillomaviruses, it is reasonable to assume similar relationships with respect to genome structure and function between animal and human papillomaviruses. Since some of the animal papillomaviruses are highly oncogenic, it is likely that all or a portion of this function may be a property of some of the HPVs as well.
Papillomaviruses (PVs) infect epithelial cells and are causative of proliferative lesions at the site of infection particularly, benign epithelial or fibroepithelial tumors (fibropapillomas), commonly known as warts. Although these viruses are generally associated with benign lesions, a specific subset of the viruses has been associated with hyperplasias capable of degenerating into intra-epithelial neoplasias and cutaneous carcinomas. The implication that these viruses may play an etiologic role in the development of some human cancers follows from numerous studies that have shown the presence of transcriptionally active human papillomavirus (HPV) deoxyribonucleic acids in a high percentage of certain cancerous lesions. Although papillomaviruses (PVs) are implicated in the etiology of cancers, the complete story of their involvement is not yet known.
Among papillomavirus infections mention should also be mad more particularly of benign dysplastic hyperproliferations of skin and mucosal epithelium such as cutaneous warts and in particular common warts and plantar warts, epidermodysplasia verruciformis (EV), plane or intermediary skin warts, and intra-epithelial neoplasias. The Papillomavirus (PV) have also been linked to widespread, serious human diseases, malignant and premalignant hyperproliferations of skin and mucosal epithelium especially; the cancers of the epidermodysplasia verruciformis (EV), oral, respiratory or laryngeal papillomatosis, focal epithelial hyperplasia, genital neoplasias and cancers of the uterine cervix (cervical carcinoma), condyloma acuminatum, cutaneous cancers, condylomas and papillomas. In addition, papillomavirus has been implicated as a causative agent in nasal tumors, and various oral cancers.
Although PVs are epitheliotropic, they also show remarkable tissue specificity and strong cellular tropism. For example, HPVs have a tropism for squamous epithelial cells and infect only surface epithelia of cutaneous and mucous membranes.
The human papillomavirus (HPV) was initially discovered in connection with benign hyperplastic (common warts and condylomata in the genital region) and pre-malignant and malignant lesions (carcinomas of the skin and vagina) of squamous epithelial neoplasms. Considerable insight into HPV biology and their involvement in human disease has been attained by the application of the techniques of molecular biology.
Infection with HPV may result in cutaneous neoplasia including common warts of the hands and feet, laryngeal warts and genital warts which may develop into genital, cervical or laryngeal carcinoma, and may be associated with as many as 90% of the condylomas and cervical carcinomas. The human papillomavirus (HPV) is also a major cause of vulvovaginal infection. The lesions from HPV are usually not described as vulvovaginitis although they do cause vulvovaginal infection. The condition is not inflammatory (vaginitis) but rather wart-like outgrowths of the tissue of the vagina, vulva and cervix and usually do not elicit any symptoms of pain or itching. But most importantly HPV is probably the most significant cause of cervical cancer in women.
Formation of an HPV-induced tumor is thought to require infection of an epithelial basal cell and the expression of viral early proteins in order to stimulate cell proliferation. The late stages of the virus life cycle, which ultimately lead to the production of infectious virions, are initiated only as the infected cell migrates through the upper differentiated layers of the epidermis.
The clinical importance of warts varies considerably and determinative factors are the infecting viral type, the location of the wart, and factors unique to the host. For example, a wart located on the skin is often clinically insignificant, being self limiting. However, warts on the vocal cords may be life threatening as a result of respiratory obstruction. Skin warts may spontaneously regress within a few years after their initial appearance but may also persist for decades. The exception is a rare life threatening papillomavirus disease termed epidermodyspasia verruciformis (EV). In this disease, the infected individual does not experience spontaneous regression, but rather the infection may progress to a malignant stage. The disease is present world-wide, but is rare and is often found among family members. Thus, genetic factors are thought to be involved in the etiology of the disease.
Warts are not just insignificant lesions, but can in the future lead to malignancies regardless of the immune status of the patient or HPV type. A possible role for HPVs in human cancer was suspected following the detection of HPV DNA genomes in tumors resulting from the malignant conversion of genital warts. Some of these HPVs have been strongly implicated as etiologic agents in dysplasia and carcinomas in the oral and genital mucosa of the infected mammal. Low risk types of HPV do not necessarily mean no risk for malignancies. High risk types of HPV and immunodeficiencies only create a greater predisposition leading to the process of malignant transformation. This phenomenon of malignant transformation is frequently seen in immunocompromised patients and in viral persistence of high risk HPV types.
Two types of precancerous changes have been characterized: the first is dysplasia, which is an impairment of the normal progress of cervical basal cells toward terminal differentiation into squamous epithelia. The second is condyloma, a wart-like precanerous change known to be of viral origin. Both dysplasia and condyloma may be induced by human papilloma viruses.
Genital warts, also referred to as venereal warts and condylomata acuminata, are one of the most serious manifestations of PV infection. As reported by the Center for Disease Control, the sexual mode of transmission of genital warts is well established and the incidence of genital warts is on the increase. Data collected from the National Therapeutic Index showed that in 1984 there were 224,900 first office visits for genital warts and 156,720 first office visits for genital herpes in the US. The incidence of genital warts has steadily increased throughout the 1970s and 1980s, as was recently demonstrated by an epidemiological study in which the mean incidence from 1950 to 1978 reached a peak of 1.065 per 1,000 populations. The prevalence of cervical HPV infection in women aged 25 to 55 proved to be 0.8%, but in 22 year old women it was 2.7%. Recent studies on cytologically normal women have demonstrated the incidence of latent infection to be 11%. Thus, there appears to be a latent stage of the disease which suggests an even greater incidence and prevalence.
The seriousness of genital warts is underlined by the recent discovery that HPV DNA can be found in all grades of cervical intraepithelial neoplasia (CIN I-III) and that a specific subset of HPV types can be found in carcinoma in situ of the cervix. Consequently, women with genital warts, containing specific HPV types are now considered at high risk for the development of cervical cancer. Currently, tens of millions of women worldwide suffer from human papilloma virus (HPV) infection of the genital tract. There is reported to be well over a million cases in the United States alone. Significant number of these women eventually develop cervical cancer of which there are about 500,000 new cases diagnosed yearly worldwide. As many as 90% of all cervical cancer maybe linked to HPV. It has been estimated that perhaps twenty percent (20%) of all cancer deaths in women worldwide are from cancers which are associated with HPV.
Whereas penile warts in males only very rarely result in cancer of the penis, when transmitted to the cervix cancer is much more likely to follow. About one-third of patients who have histologically-confirmed HPV infection of the cervix can be expected to develop cervical intraepithelial neoplasia (CIN) within a year. The lag time between infection and cancer is, however, often 10-30 years.
Condyloma acuminata is a tumor (wart) detectable on the skin or mucous membrane of the genital organs of the mammals such as men and women, and is caused by human papilloma virus (HPV). The site of infection in men is the balanic area, coronary sulcus, foreskin, anal area, urethral meatus, and in women is the vagina, labium, anal area and urethral orifice. Clinical symptoms appear from 1-6 months, on average 3 months after infection, but usually symptoms are not noticed by the patient. This wart shows distinctive papillary or cockscomb-like tumors and has a tendency to accumulate and multiply and is usually red or reddish brown in color. Genital warts are soft, flesh colored or slightly pigmented and are sexually transmitted. Chronic infections of the viruses that cause genital warts in women are a serious problem as they may develop into genital carcinoma.
Human papillomaviruses (HPVs) comprise a group of at least 75 types, based on DNA sequence homology as measured by liquid hybridization. A certain number of types of papillomavirus have already been described. Mention should be made of new types and subtypes of papillomaviruses which have been isolated from warts or disseminated macular lesions, among which some are more likely than others to give rise to the early development of cancers of the skin in patients who are infected by them. The definition of a new type is that it possesses less than 50% cross hybridisation with the DNA of known species in the liquid phase according to a standard protocol. The present invention relates to several types and subtypes of these new papillomaviruses taken individually or in combination among themselves and/or with the DNAs of previously known HPVs.
Papillomaviruses (PVs) cause epithelial tumors in humans which vary in severity depending on the site of infection and the human papilloma virus (HPV) type involved. Each HPV type exhibits host specificity, has a preferred anatomical site of infection, and can generally be associated with a specific lesion or disease. For example, HPV 1 causes benign skin tumours, verruca vulgaris or common wart, and plantar warts, whereas HPV 7 causes common and butchers' warts. Viruses infecting cutaneous surfaces are more likely to have some degree of homology to other HPVs infecting the skin than those infecting mucosal surfaces. Cutaneous infections include among others plantar wart, common wart, Butchers' common wart, flat wart, and epidermodysplasia verruciformis (EV), whereas, mucocutaneous or mucosal infections include genital wart, condyloma acuminatum, laryngeal papilloma, focal epithelial hyperplasia, and cervical carcinoma.
Further, although a particular virus type is preferentially associated with a given lesion, it may, on occasion, be found in other lesions. HPV-1 for example is associated with about 85% of plantar warts but HPV-2 has also been detected in a small percentage of plantar warts and vice versa. HPVs may be grouped with respect to sequence homology and site of infection. A non-limiting list of additional retroviruses included within the scope of the present invention is set out in Table 1.
In humans, different papillomavirus types are known to cause distinct diseases and appear at different sites in the body. For example, HPV types 1, 2, 3, 4, 7, 10 and 26-29 cause benign warts in both normal and immunocompromised individuals. HPV types 5, 8, 9, 12, 14, 15, 17, 19-25, 36 and 46-50 cause flat lesions in immunocompromised individuals. HPV types 6b, 11a, 13 and 16 are associated with lesions to mucous membranes. Cutaneous lesions, such as those induced by HPV types 5, 8, 14, 17, 20, are difficult to manage clinically, and are often associated with malignancies in immunosuppressed patients. HPV types 6, 11, 34, 39, 41-44 and 51-55 cause nonmalignant condylomata of the genital, anal, cervical or respiratory mucosa. These infections have a low risk of progression to cancer but are difficult to eradicate and are disruptive to the lives of the patients. The higher risk mucosal types 16, 18, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, and 61 cause on the other hand mainly asymptomatic flat, almost invisible lesions (flat condyloma) which can progress to high grade cervical intraepithelial neoplasia (CIN). These CIN-lesions can develop further to cervix cancer even if comparatively seldom. The highest risk of progression to malignancy is associated with lesions caused by HPV types 16, 18, 45 and 56.
HPV types 16, 18, 31 and 33 are particularly common in cervical cancers; HPV types 16 and 18 cause epithelial dysplasia of the genital mucosa and are associated with the majority of in situ and invasive malignant squamous cell carcinoma from cancer of the cervix, vagina, vulva, penis, anal canal, and Condyloma acuminata. More than 90% of all cervix cancers carry some type of HPV. HPV 16 alone is found in about 60% of all cervical tumours and about 50% of all cervical cancers indicating strong relation to the malignancy of Condyloma acuminata. These HPVs are referred to as “high risk” HPVs. HPV6 and HPV11 are two closely related viruses and most commonly detected. They are causative agents for
TABLE 1HPV-DNA DIAGNOSIS OF PAPILLOMA VIRUS INFECTIONS.HPV typeHPV Disease11, 2d, 4Common warts and mucosal warts (verrucae and plantar).22, 26, 63Common warts.33Common, mucosal, intermediary, flat, and plane warts, intra-epithelial neoplasias, cutaneous cancers, and EV.43a, 14a, 17bEpidermodysplasia verrucifonnis (EV).55, 8Flat warts, squamous cell carcinoma (SCC), intra-epithelialneoplasias, cutaneous cancers, EV and EV cancers.66Laryngeal papillomas and genital warts (condyloma)76bMucosal warts and genital warts (condyloma).87Common warts, Butchers' common warts.99, 15, 17, 19,Flat warts and epidermodysplasia verruciformis (EV).20, 21, 22, 231010Flat warts, common warts, and EV.1110a, 10bMucosal warts, common warts, intermediary warts, plane warts,intra-epithelial neoplasias, cutaneous cancers, and EV.1211Laryngeal papillomas, Condyloma (Genital warts), Condylomaacuminata.1311aMucosal warts.1412Flat warts, Intra-epithelial neoplasias and cutaneous cancers, EV andEV cancers.1513Mucosal warts, focal epithelial hyperplasia, and oral epitehlialhyperplasia (oral intraepithelial neoplasias).1614, 25, 36, 46,Flat warts47, 481714bIntra-epithelial neoplasias, EV, and EV cutaneous cancers.1816Flat warts, anal warts, mucosal warts, condyloma (genital warts),condyloma acuminate, CIN, and cervical carcinoma,1917aIntra-epithelial neoplasias, EV, and cutaneous cancers.2018CIN, genital and cervical carcinoma.2124, 50Flat warts, EV, intra-epithelial neoplasias and cutaneous cancers2227Common warts and cervical intraepithelial neoplasia (CIN)2328, 29Common, mucosal, intermediary, and plane warts, intra-epithelialneoplasias, and cutaneous cancers.2431Flat warts, cervical carcinoma, cervical intraepithelial neoplasia(CIN), oral epitehlial hyperplasia (oral intraepithelial neoplasias).2532Intra-epithelial neoplasias and cutaneous cancers.2633, 35, 45, 56,Cervical intraepithelial neoplasia (CIN) and cervical carcinoma.58, 612734, 41, 42, 43,Genital warts and laryngeal papillomas.44, 53, 542839, 51, 52Genital warts, CIN, cervical carcinoma and laryngeal papillomas.2949Common, flat, and plantar warts.3055Laryngeal papillomas, genital neoplasias and cancers of the uterinecervix, condylomas and papillomas, Genital warts, CIN.more than 90% of all condyloma (pointed genital warts) and laryngeal papillomas. These infections rarely progress to invasive cancer, and therefore these HPVs are referred to as “low risk” HPVs. In some rare cases, however, HPV6 and 11 can also be associated with CIN and cervix cancer. The most abundant subtype of HPV type 6 is HPV6a. Furthermore, HPV49 causes warts of the skin (in particular, common and plantar warts) and the differential diagnosis of epidermodysplasia verruciformis (EV). HPV50 causes epidermodysplasia verruciformis (EV), intra-epithelial neoplasias and cutaneous cancers. HPV55 causes genital neoplasias and cancers of the uterine cervix, condylomas and papillomas.
The most common disease associated with papillomavirus infection is benign skin warts. Common warts (also known as benign cutaneous warts) generally contain HPV types 1, 2, 3, 4 or 10. These warts typically occur on the soles of feet, plantar warts, or on the hands. Common skin warts are most often found in children and young adults. Later in life the incidence of common warts decreases presumably due to immunologic and physiologic changes. Plantar warts can often be debilitating and require surgical removal and they frequently reoccur after surgery. To date there is no reliable treatment for plantar warts. Common warts of the hands are unsightly but rarely become debilitating and are therefore not usually surgically treated.
Genital warts are the most frequently diagnosed, viral, sexually transmitted disease. Clinically, they may be categorized into two major groups: condyloma acuminata and flat cervical warts. Condylomas have been shown to contain virus particles and molecular studies have demonstrated that greater than 90% of these lesions contain either HPV-6 or HPV-11 DNA. Condyloma acuminata generally occur on the penis, vulva or in the perianal region. They may spontaneously regress or persist for years and progression to an invasive carcinoma occurs only at a low frequency. Unlike other genital warts, those occurring on the uterine cervix usually exhibit a flat rather than acuminate morphology, and are usually clinically detected by Pap smear. A papillomavirus etiology for cervical dysplasia was suggested by the studies of cytologists in the late 1970s who demonstrated the association on Pap smear of cytologic changes due to HPV infection with those of dysplasia. Other studies showed the presence of viral particles and viral capsid antigen in some of the dysplastic cells of these lesions. This association was important because previous clinical studies had established that cervical dysplasia (also referred to as cervical intra-epithelial neoplasia or CIN) was a precursor to carcinoma in situ which was in turn recognized to be a precursor to invasive squamous epithelial cell carcinoma (SCC) of the cervix.
A possible role for HPVs in human cancer was suspected following the detection of HPV DNA in tumors resulting from the malignant conversion of genital warts (cervical carcinoma). The cloning of two HPV genomes, HPV-16 and HPV-18 from cervical carcinomas has further stimulated research in this field of immense socio-economic importance. These were subsequently used as hybridization probes to show that more than 70% of the human cervical carcinomas and the derived cell lines scored positive for the presence of either of these HPV types. Another 20% contain additional HPV-types such as HPV-31, HPV-33, and HPV-35. Amongst these is HPV-33 which was recently cloned from an invasive cervical carcinoma using HPV-16 as a probe under conditions of reduced stringency.
Many HPV-induced lesions such as common warts, plantar warts, and flat warts are entirely benign and not clinically associated with progression to carcinomas. However, several HPVs are occasionally associated with subsequent development into squamous cell carcinomas, and HPV-5 has been associated with cutaneous carcinomas in patients with epidermodysplasia verruciformis (EV). Juvenile laryngeal papillomatosis is caused by papillomavirus HPV-11. Rare cases of spontaneous progression to invasive squamosal carcinoma of the larynx in the absence of irradiation have been described. More frequently following radiation therapy, progression of juvenile laryngeal papillomatosis progresses to squamous cell carcinoma (SCC).
Laryngeal papillomas are benign epithelial tumors of the larynx. Two HPV types, HPV-6 and HPV-11, are most commonly associated with laryngeal papillomas. Clinically, laryngeal papillomas are divided into two groups, juvenile onset and adult onset. In juvenile onset it is thought that the neonate is infected at the time of passage through the birth canal of a mother with a genital PV infection. Disease is usually manifest by age 2 and is characterized by the slow but steady growth of benign papillomas that will ultimately occlude the airway without surgical intervention. These children will typically undergo multiple surgeries with the papillomas always reoccurring. Patients will ultimately succumb to complications of multiple surgeries. To date there is no curative treatment for juvenile onset laryngeal papillomatosis and spontaneous regression is rare. Adult onset laryngeal papillomatosis is not as aggressive and will frequently undergo spontaneous remission.
Among HPV infections is epidermodysplasia verruciformis (EV). EV is a rare genetically transmitted recessive disorder which is characterized by generalized pityriasis-like lesions or disseminated flat warts that appear as small reddish macules. A variety of HPV types 3, 5, 8-10, 12-15, and 17 have been associated with EV. HPV3a and 10 which are associated with plane warts observed in some patients suffering from EV and in the population generally. DNA sequences similar to those of HPV3a have been found in a cancer of a patient suffering from EV. The genomes of HPV5 and 8 have been detected in cancers of patients suffering from EV. With the exception of types 3 and 10, this group of HPVs has not been detected in warts from healthy individuals, having only been identified in lesions from immunosuppressed renal allograft recipients. With time approximately one third of EV patients develop squamous cell carcinoma (SCC) of the skin at multiple sites. In general, SCC occurs on sun exposed areas of the skin. Only a subset of EV associated PV is consistently found in SCC. It has been reported that lesions containing HPV-5 and HPV-8 frequently undergo malignant conversion to SCC when present on sun-exposed areas. Genetic predisposition, immunologic abnormalities, and UV irradiation as well as HPV may all contribute to the development of SCC in these patients.
A number of types of papillomavirus have already been described. The framework of the present patent application includes many new types and subtypes of papillomavirus described herein and those that have not yet been discovered. The present patent also relates to mixtures or “cocktails” of DNA-HPVs isolated from the papillomaviruses which were new at that time and/or from papillomaviruses already known at the filing dates of the corresponding titles.